Nearly half of patients become non-adherent to their prescribed therapies within a year of treatment initiation. Unfortunately, the success of existing interventions to address this problem has been relatively limited, either because of the nature of the intervention or their broad applications to patients who do not require them or will not benefi from them. The efficacy of future efforts is likely to be increased by targeting interventions to non-adherent patients with poor or worsening control of their chronic conditions and tailoring interventions to individual patients based upon the willingness and ability to improve their adherence. Because the most effective interventions appear to be those that are multi-faceted and thus often complex, there is also a need for multimodal interventions that are simple and which can be integrated into routine practice. The validation of adherence measures that are not based upon administrative claims data, but which can be derived from self-reported adherence or rapidly available and routinely collected pharmacy transaction records, is also a priority. To this end, we propose a cluster randomized controlled trial (RCT) of a novel tele-pharmacist based intervention to improve adherence to medications for hypercholesterolemia, hypertension, and diabetes. This application builds on many years of research by our group on improving medication use and evaluating novel interventions in existing real-world delivery systems. The intervention will integrate the use of the electronic health record (EHR) and pharmacy claims data to identify approximately 3,000 adult patients cared for by approximately 150 primary care physicians who are both non-adherent and not achieving recommended clinical targets for glycemic, blood pressure, and cholesterol control in a real-world primary care setting. Following EHR-facilitated referral from the treating primary care physicians, a clinical pharmacist will direct an outreach program using multiple communication technologies including text messaging, secure email, mail, and video visits with the intensity of the intervention tailored to the patient's level of activation. The aims of the study are to: (1) implement and evaluate the ability of a novel tele-pharmacist intervention in a multispeciality group practice to improve adherence and clinically relevant outcomes, (2) assess the cost- effectiveness of the intervention, and (3) validate the ability to use retail pharmacy filling data and self-reported daa to evaluate adherence. Using a rigorous randomized design, we have proposed a feasible and sustainable intervention that links adherence to clinically relevant outcome measures as a core component of the program. As the nation considers substantial investments in health information technology and primary care based population management, our intervention will provide important insights into how to effectively improve medication adherence and ultimately, chronic care outcomes.